CN113995734A - Method for preparing medicine compound by centrifugal emulsification technology - Google Patents

Method for preparing medicine compound by centrifugal emulsification technology Download PDF

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CN113995734A
CN113995734A CN202111311945.1A CN202111311945A CN113995734A CN 113995734 A CN113995734 A CN 113995734A CN 202111311945 A CN202111311945 A CN 202111311945A CN 113995734 A CN113995734 A CN 113995734A
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drug
phase
liquid
oil phase
particles
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CN113995734B (en
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刘东飞
周君
白远程
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China Pharmaceutical University
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China Pharmaceutical University
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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    • A61K9/5021—Organic macromolecular compounds
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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    • A61K9/5107—Excipients; Inactive ingredients
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract

The invention discloses a method for preparing a drug compound by a centrifugal emulsification technology. Under the action of centrifugal force, the particles dispersed in the lower-density oil phase are transferred to the water phase, and a drug compound with high drug loading is prepared in one step through the rapid emulsification and solidification processes, and the compound has a certain slow release effect on the drug, so that the efficient encapsulation of the drug can be realized.

Description

Method for preparing medicine compound by centrifugal emulsification technology
Technical Field
The invention relates to a centrifugal emulsification technology for high-efficiency encapsulation of a drug, and provides a preparation method of a compound of the drug and a polymer, belonging to the technical field of pharmaceutical preparations
Background
Emulsion droplets are widely used in the fields of material manufacturing, biotechnology and pharmaceutical industry as templates, reaction vessels and drug delivery systems.[1,2]
Traditional emulsification methods, such as using rotor/stator systems, ultrasound and high pressure homogenization techniques, have high shear. These emulsification processes are uncontrollable and random, which results in poor homogeneity and poor encapsulation of the emulsion droplets produced. Furthermore, the preparation process is always accompanied by high thermal energy, which may destabilize the drug substance.
In recent years, new emulsification techniques have been developed, such as droplet microfluidics, microchannel and membrane techniques. Microfluidic technology[3]The method is a shear-based technology and is characterized in that the liquid is accurately controlled under the condition of microscale. Co-flow[4]、flow-focusing[5]And T-junction[6]Are the three main flow modes of droplet microfluidics. During this process, the continuous phase shears the dispersed phase to form dispersed phase droplets. The micro-fluidic technology usually needs to be equipped with a corresponding injection pump system and a special micro-channel, and in order to generate uniform emulsion droplets, the whole process needs to strictly maintain a stable flow rate and has poor anti-interference performance.
Microchannel emulsification techniques use precisely fabricated microchannels with well-defined geometries[7]This is a droplet generation technique based on geometry and surface tension. It is limited by low drop generation rates and parallelized solutions that increase system complexity.
With the film emulsification method, since the flow rate of the dispersed phase is low, industrialization thereof becomes a problem. In addition, emulsion droplets prepared by membrane emulsification cannot achieve good monodispersity[8]. The above modern technologies are costly, including additional pressure equipment and special designs.
The traditional emulsification method belongs to a high-energy method, the emulsification process is very violent, and the prepared emulsion droplets have poor uniformity. While the technologies such as micro-fluidic technology and membrane emulsification adopt a milder emulsification mode, but have high cost and complexity.
Researchers continue to propose new methods for encapsulating drugs using emulsification methods. CN105796508A discloses a sustained-release microsphere of insulin glargine and a preparation method thereof. The preparation method comprises the steps of preparing an organic phase and an internal aqueous phase, carrying out ultrasonic emulsification to obtain a primary emulsion, adding the primary emulsion into a polyvinyl alcohol solution, carrying out high-speed stirring to obtain a multiple emulsion, volatilizing an organic solvent, and washing the microspheres with water for injection, wherein the drug-loading rate of the prepared microspheres is 1-6%, the operation procedure in the preparation process is complex, the drug-loading rate of the microspheres is low, and the production cost is high. CN110404054A discloses an exenatide microsphere preparation, a preparation method and application thereof. The preparation method comprises preparing oil phase and water phase, shearing at high speed, preparing O/W emulsion, stirring for solidifying, washing microsphere, sieving, collecting, and drying. The drug-loading range of the prepared microspheres is 3-10%, the preparation method is complex, the drug-loading rate of the prepared microspheres is low, and the preparation process is complex.
In the aspect of technical development, the current emulsification technology shows uncontrollable emulsification process, narrow application range, high cost and incapability of realizing industrialization. In the aspect of preparation products, the currently prepared drug-containing emulsion droplets and related preparation products have low encapsulation efficiency, low drug-loading rate and poor uniformity.
Therefore, in the field of preparation, it is important to find a simple and rapid drug encapsulation technology with high encapsulation efficiency, wide application range, low cost and easy industrial production.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an encapsulation technology which is simple and quick, has high encapsulation efficiency and wide application range, is easy for industrial production and realizes the encapsulation rate close to 100 percent.
The technology has high-efficiency encapsulation performance, can utilize a very small amount of oil phase, can complete the emulsification-solidification process in one step, and realizes the quick encapsulation of particles. The carrier can be loaded with various polypeptide protein biological macromolecules and micromolecule medicines, is suitable for water-soluble or water-insoluble medicines, realizes high-efficiency entrapment and controllable slow release of the medicines, and provides a new solution for solving the entrapment problem of the water-soluble protein medicines.
The technical scheme adopted by the invention is as follows:
a method for preparing a drug compound by a centrifugal emulsification technology is characterized in that a liquid system is constructed, the system is centrifuged to obtain the drug compound, and the drug particles are efficiently wrapped. The liquid system can be two or more than three, and is suitable for any immiscible liquid with density difference, and the system formed by combining the liquids can stably exist within minutes or hours according to the density from bottom to top layer by layer.
The method for preparing the drug compound by the centrifugal emulsification technology is characterized in that the optimal combination mode of the liquid system is composed of three components, namely drug particles, liquid I and liquid II. The mass of the medicine component accounts for 0.1-99% of the mass of the whole compound.
The drug particles include common organic and inorganic material particles. The particle size is 1-1000nm, and the prepared particles can be stably dispersed in the liquid I. The liquid I is a solution consisting of the solvent I and the polymer. Wherein the polymer acts as a stabilizing agent, the polymer may stabilize the drug particles by electrostatic interaction or hydrophobic interaction with the particles.
The solvent I is a good solvent of the polymer stabilizer and is a poor solvent of the active pharmaceutical ingredient.
The liquid I and the liquid II are immiscible or partially miscible, and can be stably layered within a certain time to form a two-phase system.
The density relation among the particles, the liquid I and the liquid II is as follows: particles > liquid II > liquid I.
The two immiscible liquids with different densities can stably disperse the drug particles and dissolve the polymer. The high density phase liquid is a poor solvent for the polymer and is generally such that liquid I has a density less than or equal to that of liquid II.
The drug particles are transferred from one phase of liquid to another. Therefore, a certain amount of centrifugal force is required.
The fluid system is suitable for use in any centrifuge or device that provides centrifugal force and is not limited by the type of centrifuge instrument on the market.
The liquid system described is suitable for any apparatus including all centrifuge tubes and containers of corresponding volume on the market.
The drug compound can be uncured composite milk or a cured compound or a mixture of two substances. The properties of the product can be adjusted by adjusting the mutual solubility between the solvents.
The drug compound can be adjusted by a device to prepare a compound with any geometric shape such as a sphere shape, a rod shape and the like, so as to adjust the release characteristics and the like of the product.
The liquid system can add certain surface active agent into two-phase liquid to reduce interfacial tension and regulate and control drug encapsulation effect.
In the liquid system, salt can be added into the two-phase liquid to adjust the intersolubility of the two phases, and the diffusion speed between the two phases and the curing speed of the compound can be adjusted, so that the release characteristic of the product can be adjusted.
In the liquid system, a density regulator (sugar, salt and the like) can be added into the two-phase liquid to regulate the density of the water phase, so as to form a stable two-phase system.
The drug particles comprise one or more of polypeptide protein biological macromolecule drugs, micromolecular drug water-soluble drugs and water-insoluble drugs.
The polypeptide protein biological macromolecule medicine comprises one or more of insulin (insulin), insulin analogues, interferon (interferon), Ovalbumin (OVA), recombinant human growth hormone (rhGH), glucagon-like peptide (GLP), glucagon-like peptide analogues, immunoglobulin (IgG), programmed death receptor 1(PD-1), cell type death-ligand (PD-L1) and the like.
The small molecule drug comprises one or more of bupivacaine, bupivacaine medicinal salt (such as bupivacaine hydrochloride and the like), lidocaine medicinal salt (such as lidocaine hydrochloride and the like), mepivacaine medicinal salt (such as mepivacaine hydrochloride and the like), procaine medicinal salt (such as procaine hydrochloride and the like) and the like.
The water-insoluble medicine comprises one or a mixture of more of tretinoin, methotrexate, teniposide, minocycline, amphotericin B, griseofulvin, flurbiprofen, indomethacin, ibuprofen, naproxen, spironolactone, estradiol, vitamin A, vitamin D, vitamin E, ursolic acid and oleanolic acid.
The liquid system may be a combination system of one or more organic solvents and inorganic solvents.
The organic solvent comprises any one or a mixture of more of methanol, ethanol, ethylene glycol, diethylene glycol, isopropanol, 1-propanol, 1, 2-propanediol, 1, 3-propanediol, butanol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 1, 5-pentanediol, 2-butoxyethanol, glycerol, methyldiethanolamine, diethanolamine, acetone, acetonitrile, diethylenetriamine, dimethoxyethane, ethylamine, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetaldehyde, pyridine, triethylene glycol, ethyl acetate, dimethyl carbonate, dichloromethane, cyclohexane, n-octanol or chloroform.
The polymer comprises one or a mixture of more of hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose phthalate acetate, methyl cellulose phthalate acetate, hydroxypropyl methyl cellulose acetate phthalate, opadry polymer, Neutreli polymer, Sutely polymer, acetylated dextran and derivatives thereof, polylactic acid-glycolic acid copolymer and polylactic acid/polyethylene glycol block copolymer; the polymer with strong hydrophobic effect comprises one or more of polyethylene glycol, hydrophobic chitosan and poloxamer (F127, F68) and derivatives thereof.
One of the liquids is an inorganic solvent. According to different preparation purposes, different ions and molecules can be added to the water phase as a density regulator to regulate the density of the water phase. Or a surfactant may be added to adjust the interfacial tension.
The centrifugal emulsification technology and the preparation method of the compound of the medicine and the polymer are characterized by comprising the following steps:
(1) preparation of the oil phase
Firstly, mixing a solution formed by dissolving a medicament in a good solvent of the medicament with a poor solvent of the medicament to form particles of the insoluble medicament; mixing the obtained particle dispersion with a flocculating agent to flocculate and precipitate the drug particles; discarding the supernatant, and dispersing the insoluble drug component particles in a solution composed of a stabilizer with electric property opposite to that of the drug or hydrophobic effect and a good solvent of the stabilizer to form a drug particle dispersion, namely an oil phase.
(2) Construction of a two-phase system: and (2) carrying out ultrasonic treatment on the oil phase obtained in the step (1), stably dispersing the particles in the oil phase by utilizing the interaction between the polymer and the particles, and adding the oil phase into the upper layer of the water phase to obtain an oil-water two-phase composite system.
(3) Centrifuging the composite system and collecting the composite
In the centrifugal equipment, the whole composite system is centrifugally operated at a certain rotating speed. And then, removing the water phase and the oil phase, taking out the compound solidified at the bottom, and drying to obtain the product.
The preparation method of the centrifugal emulsification technology platform and the compound of the medicine and the polymer thereof is characterized in that the preparation of the particles comprises the following steps: the method comprises the following steps: physical and chemical and physical-chemical methods to obtain micron or nanometer level particles, such as common precipitation method, pulverization method, synthesis method, etc. The surface of the particles should have certain wettability with the oil phase, and if the surface of the particles is not wettable, the surface of the particles can be modified by electrostatically adsorbing polymers with opposite charges in the oil phase.
The best scheme is as follows:
1. the drug concentration is 20mg/mL
2. Polymer type and concentration 40mg/mL PLGA-SP (502H)
3. The centrifugal speed is 4000rpm
4. The water phase is 2% PVA water solution
The benign solvent of the present invention means that 1g of solute can be completely dissolved in less than 100ml of solvent.
The poor solvent of the invention means that 1g of solute can be completely dissolved in more than 1000ml of solvent.
The difficulty of the invention lies in that:
1. in the aspect of adsorption action: the electrostatic interaction of the particles with the polymer needs to be of a certain strength to enable the polymer to be firmly adsorbed on the particle surface.
2. In the aspect of centrifugal force: centrifugal force of a certain magnitude is needed to transfer particles from one phase to another phase, and the drug compound with high drug loading capacity is prepared in one step through a rapid emulsification and solidification process.
3. Liquid system aspect: a certain density difference between the two liquids is required to be not completely miscible, so as to construct a liquid system.
Principle of action and points of innovation
1. The action principle is as follows:
as shown in fig. 9, the present invention makes polymer molecules adsorbed around drug particles through electrostatic interaction between the drug and the polymer, and at the same time, the polymer molecules have oil solubility, so that organic solvent is carried around the polymer, and finally the solvent is adsorbed on the particle surface, thereby realizing 'solvation' of the particles; and then transferring the particles from the oil phase to the water phase by using the action of centrifugal force to realize centrifugal emulsification.
2. The innovation points are as follows:
the invention utilizes the adsorption effect of the particles on liquid for the first time, provides a simple and efficient emulsification technology, and can be used for efficient entrapment of medicaments.
Advantageous effects
1. The invention relates to a centrifugal emulsification technology platform and a preparation method of a compound of a drug and a polymer thereof. The particle-mediated emulsification mode is put forward for the first time, oil-in-water type emulsion can be generated by using a very small amount of oil phase, the consumption of organic solvent is very low, the emulsification-solidification can be realized by one step, and the emulsification efficiency is very high.
2. The centrifugal emulsification technology platform and the preparation method of the compound of the drug and the polymer thereof realize the complete encapsulation of each drug particle, and the encapsulation efficiency is extremely high and can reach 90-100%.
3. The centrifugal emulsification technology platform and the preparation method of the compound of the medicine and the polymer can be realized on common centrifugal equipment without special devices and equipment, and have the advantages of simple universality, high preparation speed and easy industrial production.
4. The centrifugal emulsification technology platform and the preparation method of the compound of the drug and the polymer thereof have no requirement on the charged types of the drug components, can be suitable for all the drug components with isoelectric points larger than or smaller than 7, have wide selection range of the drug components and have universality.
5. The centrifugal emulsification technology platform and the preparation method of the compound of the drug and the polymer do not have the necessary requirement on whether the stabilizer has charges or not, can be stabilized through various actions such as hydrophobic action and the like, and have wide selection range.
Drawings
FIG. 1 is a polarization micrograph of an AC-DEX-SP encapsulated bovine serum albumin solid prepared under the conditions of example 19.
FIG. 2 is a polarized light micrograph of PLGA-SP coated insulin solid prepared under the conditions of example 3;
FIG. 3 is a polarized light micrograph of PLGA-SP coated insulin solid prepared under the conditions of example 31;
figure 4 effect release profile of insulin of example 7;
FIG. 5 Effect insulin release profile of example 8;
FIG. 6 Effect insulin release profile of example 9;
FIG. 7 Effect insulin release profile of example 10;
figure 8 effect release profile of insulin from example 11.
Fig. 9 is a schematic diagram of the principle of the present invention.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
General methods of preparing microspheres: solvent evaporation method
Solvent volatilization method: the polymeric material is first dissolved in an organic solvent and the drug is dispersed or dissolved in the solution to form a dispersion or solution, which is then emulsified in the aqueous phase to form droplets. The organic solvent is firstly diffused into the water phase, then is volatilized into the air phase, the emulsion drops begin to solidify into balls along with the volatilization of the organic solvent, and the microspheres can be prepared by filtering, washing and drying.
Cited patents: CN105796508A discloses sustained-release microspheres of insulin glargine, microspheres injection of insulin glargine and preparation methods thereof. The preparation method comprises the steps of preparing an organic phase and an internal aqueous phase, carrying out ultrasonic emulsification to obtain a primary emulsion, adding the primary emulsion into a polyvinyl alcohol solution, carrying out high-speed stirring to obtain a multiple emulsion, volatilizing an organic solvent, and washing the microspheres with water for injection, wherein the drug-loading rate of the prepared microspheres is 1-6%, the operation procedure in the preparation process is complex, the drug-loading rate of the microspheres is low, and the production cost is high. The nanoparticles provided by the embodiment of the invention are prepared by adopting a CN105796508A method.
Example 1
Insulin nanoparticles (20mg/mL) were dispersed in ethyl acetate solution, AC-DEX-SP (40mg/mL) was added, after complete dissolution, sonication yielded a stably dispersed oil phase (0.5mL), which was then added to the upper layer of 30 volumes of aqueous phase (15mL) and centrifuged horizontally for 10min at 4000 rpm. A white solid was obtained.
Example 2
Insulin nanoparticles (20mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,40mg/mL) is added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 3
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) is added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 4
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,10mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 5
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,15mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 6
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,20mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 7
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,30mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 8
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,40mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 9
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,50mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 10
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,100mg/mL) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 11
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,10mg/mL) and PLGA (502H,10mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.4mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume being 30 times of that of the oil phase, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 12
Insulin nanoparticles (20mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,20mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.8mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume being 30 times of the volume, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 13
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,5mg/mL) and PLGA (502H,5mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.4mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume being 30 times of that of the oil phase, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 14
Insulin nanoparticles (20mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H,10mg/mL) and PLGA (502H,10mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.4mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of water phase (15mL) with the volume being 30 times of the volume, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 15
Exenatide nanoparticles (50mg/mL) are dispersed in an ethyl acetate solution, PLGA-SP (502H,25mg/mL) and PLGA (502H,25mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 16
The exenatide nanoparticle (20mg/mL) is dispersed in ethyl acetate solution, PLGA-SP (502H,20mg/mL) and PLGA (502H,20mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the stable dispersed oil phase is added to the upper layer of water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 17
Exenatide nanoparticles (25mg/mL) are dispersed in an ethyl acetate solution, PLGA-SP (502H,25mg/mL) and PLGA (502H,25mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 18
Exenatide nanoparticles (25mg/mL) are dispersed in an ethyl acetate solution, PLGA-SP (502H,12.5mg/mL) and PLGA (502H,12.5mg/mL) are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the stable dispersed oil phase is added to an upper layer of a water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 19
Dispersing bovine serum albumin nanoparticles (20mg/mL) in an ethyl acetate solution, adding AC-DEX-SP (40mg/mL), completely dissolving, performing ultrasonic treatment to obtain a stably dispersed oil phase (0.5mL), adding the oil phase into an upper layer of a water phase (15mL) with the volume of 30 times, and horizontally centrifuging for 10min at the rotation speed of 4000 rpm. A white solid was obtained. (FIG. 1)
Example 20
Insulin nanoparticles (20mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (DG080-1:8) and 40mg/mL are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 21
Insulin nanoparticles (20mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (DG080-1:24) and 40mg/mL are added, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL) with the volume of 30 times, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 22
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL, 2% PVA aqueous solution) with the volume 15 times, and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 23
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL, pure water) with the volume 15 times, and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 24
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (504H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL, 2% PVA aqueous solution) with the volume 15 times, and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 25
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (504H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a water phase (15mL, pure water) with the volume 15 times, and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 26
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of 15 times volume of water phase (15mL, 2% PVA aqueous solution and 5% MgCl 2.6H2O) and horizontally centrifuged for 20min at the rotation speed of 4000rpm and then at 20000rpm for 120 min. A white solid was obtained.
Example 27
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (504H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of 15 times volume of water phase (15mL, 2% PVA aqueous solution and 5% MgCl 2.6H2O) and horizontally centrifuged for 20min at the rotation speed of 4000rpm and then at 20000rpm for 120 min. A white solid was obtained.
Example 28
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a 15-time volume water phase (15mL, 4% PVA aqueous solution) and horizontally centrifuged for 20min at the rotating speed of 4000rpm and then 120min at 20000 rpm. A white solid was obtained.
Example 29
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a 15-time volume water phase (15mL, 2% F-127 aqueous solution) and horizontally centrifuged for 20min at the rotating speed of 4000rpm and then 120min at 20000 rpm. A white solid was obtained.
Example 30
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a 15-time volume water phase (15mL, 2% Tween 80 aqueous solution) and horizontally centrifuged for 20min at the rotating speed of 4000rpm and then 120min at 20000 rpm. A white solid was obtained.
Example 31
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (502H) and 20mg/mL are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a 15-time volume water phase (15mL, 2% Tween 20 aqueous solution) and horizontally centrifuged for 20min at the rotating speed of 4000rpm and then 120min at 20000 rpm. A white solid was obtained.
Example 32
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP (Mw:110k,20mg/mL) is added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of a 15-fold volume aqueous phase (15mL, 2% PVA aqueous solution + 5% MgCl 2.6H2O), and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000rpm to obtain white solid.
Example 33
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP 20mg/mL (Mw:110k) and PLGA 20mg/mL (Mw:110k) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of 15 times volume of water phase (15mL, 2% PVA aqueous solution + 5% MgCl 2.6H2O), and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000rpm, so that white solid is obtained.
Example 34
Insulin nanoparticles (10mg/mL) were dispersed in ethyl acetate solution, PLGA-SP 20mg/mL (Mw:110k) was added, after complete dissolution, a stably dispersed oil phase (1mL) was obtained after sonication, followed by addition of a 15-fold volume of the upper layer of aqueous phase (15mL, 2% aqueous PVA + 5% MgCl 2.6H2O), horizontal centrifugation for 20min at 4000rpm, followed by centrifugation at 20000rpm for 120 min. A white solid was obtained.
Example 35
Insulin nanoparticles (10mg/mL) are dispersed in ethyl acetate solution, PLGA-SP 20mg/mL (Mw:110k) and PLGA 20mg/mL (Mw:110k) are added, after complete dissolution, stable dispersed oil phase (1mL) is obtained after ultrasonic treatment, and then the oil phase is added to the upper layer of 15 times volume of water phase (15mL, 2% PVA aqueous solution + 5% MgCl 2.6H2O), and the mixture is horizontally centrifuged for 20min at the rotating speed of 4000rpm and then centrifuged for 120min at the rotating speed of 20000 rpm. A white solid was obtained.
Example 36
Lidocaine nanoparticles (20mg/mL) are dispersed in an ethyl acetate solution, PLGA-SP (502H) is added, the concentration of a polymer is 40mg/mL, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the oil phase is added to an upper layer of a water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 37
Bupivacaine nanoparticles (20mg/mL) are dispersed in an ethyl acetate solution, PLGA-SP (502H) is added, the concentration of a polymer is 40mg/mL, after complete dissolution, stable dispersed oil phase (0.5mL) is obtained after ultrasonic treatment, and then the stable dispersed oil phase is added to an upper layer of a water phase (15mL) with the volume being 30 times that of the upper layer, and the mixture is horizontally centrifuged for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 38
Dispersing ursolic acid nanoparticles (20mg/mL) in an ethyl acetate solution, adding PLGA-SP (502H) to obtain a polymer with the concentration of 40mg/mL, performing ultrasonic treatment to obtain a stably dispersed oil phase (0.5mL) after the polymer is completely dissolved, then adding the stably dispersed oil phase to an upper layer of a water phase (15mL) with the volume of 30 times, and horizontally centrifuging for 10min at the rotating speed of 4000 rpm. A white solid was obtained.
Example 39
Dispersing oleanolic acid nanoparticles (20mg/mL) in an ethyl acetate solution, adding PLGA-SP (502H) with a polymer concentration of 40mg/mL, completely dissolving, performing ultrasonic treatment to obtain a stably dispersed oil phase (0.5mL), adding the oil phase to an upper layer of a water phase (15mL) with a volume of 30 times, horizontally centrifuging for 10min, and rotating at 4000 rpm. A white solid was obtained.
Effect example 1
This example examines the effect of different polymers on the amount of insulin loaded in the prepared solid form in examples 1 and 2. And (3) respectively and completely dissolving the white solid prepared by the formula in DMSO, measuring the content of insulin by using a high performance liquid phase, and calculating to obtain the drug loading rate of the insulin. (Table 1)
TABLE 1
Figure BDA0003341949740000101
The results show that the insulin load of the product made from both polymers is high. At the same concentration, PLGA-SP is used as a polymer, and the drug loading of the prepared product is higher. Therefore, PLGA-SP may be a preferred type of polymer.
Effect example 2
This example examines the effect of the amount of additional PLGA added on the amount of insulin load in the prepared solid form in examples 3, 4, 5, 6, 7, 8, 9, 10. And (3) respectively and completely dissolving the white solid prepared by the formula in DMSO, measuring the content of insulin by using a high performance liquid phase, and calculating to obtain the drug loading rate of the insulin. (Table 2)
TABLE 2
Figure BDA0003341949740000102
The result shows that the addition of PLGA with a certain concentration into the oil phase has obvious influence on the drug loading of insulin. The more PLGA is added, the lower the drug loading rate is, and finally the adjustment of the drug loading rate in the range of 4-70% is realized. Therefore, the regulation and control of the product can be realized by adjusting the adding concentration of PLGA, wherein the highest drug loading rate is 10mg/mL of drug concentration and 20mg/mL of polymer concentration.
Effect example 3
This example examines the effect of oil phase volume on drug and polymer concentration ratio on the amount of insulin loaded in the prepared solid form in examples 11, 12, 13, and 14. And (3) respectively and completely dissolving the white solid prepared by the formula in DMSO, measuring the content of insulin by using a high performance liquid phase, and calculating to obtain the drug loading rate of the insulin. (Table 3)
TABLE 3
Figure BDA0003341949740000111
The results show that the oil phase volume changes from 0.4mL to 0.8mL and the drug load changes from 40.41% to 44.41%, i.e. the oil phase volume has little effect on the drug load of insulin. When the ratio of polymer to drug is from 2: 1 to 1: at 1, the drug loading rate was changed from 44.41% to 82.60%, i.e., the drug-aggregating concentration ratio had a large influence on the drug loading rate. Wherein, the preparation conditions with the highest drug loading are as follows: the ratio of polymer to drug was 1: 1, drug and polymer concentrations were 20 mg/mL.
Effect example 4
This example examines the effect of drug and polymer concentrations on exenatide drug loading in the prepared solid in examples 15, 16, 17, 18. And (3) respectively completely dissolving the white solid prepared by the prescription in DMSO, measuring the content of insulin by using a high performance liquid phase, and calculating to obtain the drug loading capacity of the exenatide. (Table 4)
TABLE 4
Figure BDA0003341949740000112
The results show that drug and polymer concentrations have some effect on exenatide drug loading. The higher the drug and polymer concentration, the higher the drug loading. Wherein, the preparation condition of the highest drug loading is that the concentration of the polymer and the drug is 50 mg/mL.
Effect example 5
This example examines the effect of the type and modification of the polymer on the amount of insulin loaded in the prepared solid form in examples 1, 2, 20 and 21. And (3) respectively and completely dissolving the white solid prepared by the formula in DMSO, measuring the content of insulin by using a high performance liquid phase, and calculating to obtain the drug loading rate of the insulin. (Table 5)
TABLE 5
Figure BDA0003341949740000113
The results show that different types of PLGA have small influence on the drug loading rate and the encapsulation efficiency of the insulin. The AC-DEX-SP and PLGA-SP have a large influence on the drug loading and encapsulation efficiency of insulin. Wherein, the highest drug loading is PLGA-SP (502H) which can reach 90.68 percent, and the highest entrapment rate is AC-DEX-SP which can reach 98.97 percent.
Effect example 6
In this example, the influence of different small molecule drugs as model drugs on the drug loading and encapsulation efficiency of solid materials in examples 36, 37, 38 and 39 was examined. And (3) respectively completely dissolving the white solid prepared by the prescription in DMSO, measuring the content of the medicine by using a high performance liquid phase, and calculating to obtain the medicine-loading rate. (Table 6)
TABLE 6
Figure BDA0003341949740000121
The result shows that the drug-loading rate and the encapsulation rate of the water-soluble micromolecule are lower than those of the insoluble micromolecule, wherein the highest drug-loading rate is ursolic acid which can reach 77.87%; the highest encapsulation efficiency is oleanolic acid, and can reach 96.71%.
Effect example 7
This example examines the effect of the aqueous phase ingredients on the in vitro release of insulin from the prepared solid in examples 22, 23, 24, 25. The white solid prepared by the above formulation was placed in 1M PBS solution, and the release curve of insulin was measured and plotted at 37 deg.C (FIG. 4).
The results show that the ingredients in the aqueous phase have a significant effect on insulin release. Of these, 504H released the slowest under the conditions of the preparation in water. PLGA-502H as a polymer is released most quickly under the condition that the water phase is prepared in pure water, and the release amount reaches about 50% in 250 hours.
Effect example 8
This example examines the effect of PLGA type on the in vitro release of insulin from prepared solids in examples 26 and 27. The white solid prepared by the above recipe was put in 1M PBS solution, and the release curve of insulin was measured and plotted at 37 ℃ as shown in FIG. 5.
The results indicate that the type of PLGA has an effect on the release of insulin. Wherein release of 504H is relatively slower than release of 502H. At 240H, 504H was released at about 20%, while 502H was released at about 50%.
Effect example 9
This example examines the effect of different surfactant types on the in vitro release of insulin from prepared solids in examples 28, 29, 30, 31. The white solid prepared by the above formulation was placed in 1M PBS solution, and the release curve of insulin was measured and plotted at 37 ℃ as shown in FIG. 6.
The results show that different surfactants have some effect on insulin release, with the burst release of F-127 and Tween 80 being less than that of PVA and Tween 20. The slowest released was 2% tween 80 and the fastest released was 2% tween 20.
Effect example 10
This example examines the effect of additional PLGA addition on the in vitro release of insulin from the prepared solid in examples 32, 33. The white solid prepared by the above formulation was placed in 1M PBS solution, and the release curve of insulin was measured and plotted at 37 ℃ as shown in FIG. 7.
The results show that the addition of PLGA significantly slowed the release of insulin. Wherein the final release of not added PLGA reaches 65%, and the final release of added PLGA reaches 55%.
Effect example 11
This example examines the effect of PLGA addition under high speed centrifugation conditions on the in vitro release of insulin from the prepared solid in examples 34 and 35. The white solid prepared by the above formulation was placed in 1M PBS solution, and the release curve of insulin was measured and plotted at 37 ℃ as shown in FIG. 8.
The results show that the addition of PLGA has a certain influence on the insulin release degree under the condition of high-speed centrifugation. Wherein the insulin without added PLGA reaches a maximum release of about 99% before 100 h. The insulin added with PLGA reached a maximum release of about 93% after 200 h.
Reference to the literature
[1]Lu,W.,Kelly,A.L.&Miao,S.Emulsion-based encapsulation and delivery systems for polyphenols.Trends in Food Science&Technology 47,1-9,doi:10.1016/j.GIFs.2015.10.015(2016).
[2]Zhao,C.-X.Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery.Adv.Drug Deliv.Rev.65,1420-1446,doi:10.1016/j.addr.2013.05.009(2013).
[3]Gelin,P.et al.Microfluidic device for high throughput production of monodisperse droplets.Industrial&Engineering Chemistry Research,doi:10.1021/acs.iecr.9b05935(2020).
[4]Taassob,A.,Manshadi,M.K.D.,Bordbar,A.,Kamali,R.J.J.o.t.B.S.o.M.S.&Engineering.Monodisperse non-Newtonian micro-droplet generation in a co-flow device.39,2013-2021(2017).
[5]Wu,T.et al.Monodisperse droplets by impinging flow-focusing.21,129(2017).
[6]Chakraborty,I.,Ricouvier,J.,Yazhgur,P.,Tabeling,P.&Leshansky,A.J.P.o.F.Droplet generation at Hele-Shaw microfluidic T-junction.31,022010(2019).
[7]Khalid,N.,Kobayashi,I.,Neves,M.A.,Uemura,K.&Nakajima,M.Microchannel emulsification:A promising technique towards encapsulation of functional compounds.Crit.Rev.Food Sci.Nutr.58,2364-2385,doi:10.1080/10408398.2017.1323724(2018).
[8]
Figure BDA0003341949740000131
G.T.,Kobayashi,I.&Nakajima,M.Production of uniform droplets using membrane,microchannel and microfluidic emulsification devices.Microfluidics and Nanofluidics 13,151-178,doi:10.1007/s10404-012-0948-0(2012).

Claims (9)

1. A method for preparing a drug compound by a centrifugal emulsification technology is characterized in that a liquid system is constructed, and the system is centrifuged to obtain the drug compound; the liquid system is two or more than three, and is suitable for any immiscible liquid with density difference, and the system formed by combining the liquids can stably exist within minutes or hours by stacking from bottom to top according to the density.
2. The method of claim 1, wherein the liquid system comprises drug particles, liquid I and liquid II, wherein the liquid I and liquid II are immiscible or partially miscible liquids with different densities; the mass of the medicine particles accounts for 0.1-99% of the mass of the whole compound;
the liquid I is a solution consisting of a polymer and a solvent I, wherein the polymer is used as a stabilizing agent; the solvent I is a good solvent of the polymer and is a poor solvent of the medicine components in the medicine particles.
3. The method of claim 2, wherein the density relationship of the drug particles, the fluid I and the fluid II is: drug particles > liquid II > liquid I.
4. The method of claim 3, wherein a density modifier is added to the two-phase liquid to adjust the density of the aqueous phase, thereby forming a stable two-phase system, wherein the density modifier is sugar or salt.
5. The method for preparing a drug complex by centrifugal emulsification technique according to any one of claims 1 to 4, wherein the drug particles comprise one or more of polypeptide protein type biomacromolecule drugs, small molecule drugs water-soluble drugs and water-insoluble drugs.
6. The method of claim 5, wherein the polypeptide protein-based biomacromolecule drug comprises one or more of insulin, interferon, Ovalbumin (OVA), recombinant human growth hormone, glucagon-like peptide, immunoglobulin, programmed death receptor 1, and a cellular apoptosis-ligand;
the small molecule medicine comprises one or more of bupivacaine, bupivacaine medicinal salt, lidocaine medicinal salt, mepivacaine medicinal salt, procaine and procaine medicinal salt;
the water-insoluble medicine comprises one or a mixture of more of tretinoin, methotrexate, teniposide, minocycline, amphotericin B, griseofulvin, flurbiprofen, indomethacin, ibuprofen, naproxen, spironolactone, estradiol, vitamin A, vitamin D, vitamin E, ursolic acid and oleanolic acid.
7. The method of claim 2, wherein the liquid I is any one or more of methanol, ethanol, ethylene glycol, diethylene glycol, isopropanol, 1-propanol, 1, 2-propanediol, 1, 3-propanediol, butanol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 1, 5-pentanediol, 2-butoxyethanol, glycerol, methyldiethanolamine, diethanolamine, acetone, acetonitrile, diethylenetriamine, dimethoxyethane, ethylamine, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetaldehyde, pyridine, triethylene glycol, ethyl acetate, dimethyl carbonate, dichloromethane, cyclohexane, n-octanol, and chloroform;
the liquid II is water.
8. The method for preparing a pharmaceutical composition according to claim 2, wherein the polymer comprises at least one selected from the group consisting of hypromellose acetate succinate, cellulose acetate trimellitate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, opadry polymers, neurally polymers, sutre polymers, acetylated dextran and its derivatives, polylactic acid-glycolic acid copolymer and polylactic acid/polyethylene glycol block copolymer, polyethylene glycol, hydrophobic chitosan and poloxamer.
9. A method of preparing a pharmaceutical composition according to any one of claims 1 to 8 by centrifugal emulsification comprising the steps of:
(1) preparation of the oil phase
Firstly, mixing a solution formed by dissolving a medicament in a good solvent of the medicament with a poor solvent of the medicament to form particles of the insoluble medicament; mixing the obtained particle dispersion with a flocculating agent to flocculate and precipitate the drug particles; removing the supernatant, and dispersing the insoluble drug component particles in a solution composed of a stabilizer with electric property opposite to that of the drug or hydrophobic effect and a good solvent of the stabilizer to form a drug particle dispersion liquid, namely an oil phase;
(2) construction of a two-phase system: performing ultrasonic treatment on the oil phase obtained in the step (1), stably dispersing particles in the oil phase by utilizing the interaction between a polymer and the particles, and adding the oil phase to the upper layer of the water phase to obtain an oil-water two-phase composite system;
(3) centrifuging the composite system and collecting the composite
In centrifugal equipment, carrying out centrifugal operation on the whole composite system at a certain rotating speed; and then, removing the water phase and the oil phase, taking out the compound solidified at the bottom, and drying to obtain the product.
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CN107375238A (en) * 2016-05-16 2017-11-24 刘东飞 A kind of superelevation medicine-carried nano particles and preparation method thereof
CN109700780A (en) * 2019-01-31 2019-05-03 浙江圣兆药物科技股份有限公司 A kind of water-soluble drug sustained release microsphere of high encapsulation rate and preparation method thereof
CN112603892A (en) * 2020-12-18 2021-04-06 中国药科大学 Drug-loaded microsphere and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1270985A (en) * 1999-04-21 2000-10-25 于焕春 Continuous heavy oil emulsifying process
CN107375238A (en) * 2016-05-16 2017-11-24 刘东飞 A kind of superelevation medicine-carried nano particles and preparation method thereof
CN109700780A (en) * 2019-01-31 2019-05-03 浙江圣兆药物科技股份有限公司 A kind of water-soluble drug sustained release microsphere of high encapsulation rate and preparation method thereof
CN112603892A (en) * 2020-12-18 2021-04-06 中国药科大学 Drug-loaded microsphere and preparation method thereof

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